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Mycobacterium avium-intracellulare (MAI) / MAC

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1. Microbiology & Classification

• Family: Mycobacteriaceae; Genus: Mycobacterium
• MAC = a group of closely related nontuberculous mycobacteria (NTM), primarily:
  • Mycobacterium avium
  • Mycobacterium intracellulare
  • Mycobacterium paratuberculosis (and others)
• Staining: Acid-fast bacilli (AFB) — positive on Ziehl-Neelsen and auramine-rhodamine stains
• Growth: Slow-growing (colonies appear in 2–4 weeks); grows at 37°C; non-chromogenic
• Morphology: Slightly curved, rod-shaped organisms; intracellular pathogen — survives within macrophage phagolysosomes by inhibiting phagolysosomal fusion
• Serovars: >28 serovars identified; serovars 1–6 predominantly cause human disease

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2. Epidemiology

• Ubiquitous environmental organism: found in soil, water (including tap water, hot tubs, swimming pools), aerosols, animals, and food
• Not transmitted person-to-person; acquired from environmental exposure
• In the United States, NTM infections outnumber M. tuberculosis infections and are an important cause of pulmonary morbidity in adults
• The number of known NTM species grew from 50 (1997) to >125 (2006), with MAC remaining the most clinically significant
• Increasing incidence observed in some U.S. regions and globally
• Disseminated MAC is rare in immunocompetent individuals; primarily affects immunocompromised hosts

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3. Pathogenesis

• Entry via inhalation (respiratory tract) or ingestion (gastrointestinal tract)
• Organisms are phagocytosed by macrophages but resist intracellular killing:
  • Inhibit phagolysosome acidification
  • Produce glycopeptidolipids (GPL) that impair macrophage activation
  • Down-regulate TNF-α and IL-12 production
• In immunocompetent hosts → granuloma formation contains infection
• In HIV/AIDS or severe immunosuppression (CD4 <50 cells/μL) → uncontrolled macrophage infection → disseminated disease

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4. Clinical Syndromes

A. Pulmonary MAC Disease (most common in immunocompetent hosts)

Characteristic CT pattern includes bronchiectasis and tree-in-bud pattern (bronchiolar inflammation), distributed in both lungs, particularly the middle lobe and lingula.

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B. Disseminated MAC (DMAC) — primarily in HIV/AIDS

• Occurs when CD4 count <50 cells/μL
• Symptoms: High spiking fevers, drenching night sweats, profound weight loss, fatigue, anorexia
• Signs: Hepatosplenomegaly, lymphadenopathy, anemia, elevated alkaline phosphatase
• Bacteremia: Organisms are recoverable from blood cultures (lysis-centrifugation or BACTEC)
• Without ART and prophylaxis, incidence was ~40% per year in advanced AIDS

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C. Lymphadenitis (Scrofula)

• Primarily in immunocompetent children (ages 1–5 years)
• Unilateral, painless cervical or submandibular lymphadenopathy
• Skin may become violaceous; fistula formation possible
• Diagnosis: Excisional biopsy (preferred over FNA)

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D. Hypersensitivity/Hot Tub Lung

• Non-infectious, granulomatous hypersensitivity pneumonitis from aerosolized MAC (hot tubs, showers)
• Presents with dyspnea, cough, fever after hot tub exposure
• Ground-glass opacities on CT; responds to antigen avoidance ± steroids

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5. Diagnosis

Pulmonary MAC (ATS/IDSA Diagnostic Criteria)

1. Clinical: Pulmonary symptoms with nodular or cavitary opacities on CXR, or HRCT bronchiectasis with multiple small nodules — after excluding other diagnoses
2. Microbiologic (any of):
   • ≥2 positive sputum cultures (separate specimens), OR
   • ≥1 positive bronchial wash/lavage culture, OR
   • Transbronchial or lung biopsy with mycobacterial histopathology + positive culture
3. Expert consultation recommended

Disseminated MAC

• Blood cultures (mycobacterial — lysis-centrifugation method or BACTEC MYCO/F Lytic): high sensitivity
• Bone marrow biopsy: granulomas with AFB
• Liver biopsy: granulomatous hepatitis
• CBC: normocytic anemia, elevated ESR, elevated ALP
• Identification: DNA probes, HPLC of mycolic acids, 16S rRNA sequencing

Lymphadenitis

• Excisional biopsy: caseating granulomas with AFB; culture for definitive ID

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6. Treatment

Pulmonary MAC — ATS/IDSA 2020 Guidelines

• Duration: Until sputum culture-negative for 12 months
• Amikacin (IV or inhaled liposomal amikacin) added for severe/refractory disease
• Bedaquiline emerging as option for macrolide-resistant MAC

Disseminated MAC (HIV/AIDS)

• Azithromycin 500–600 mg/day + Ethambutol 15 mg/kg/day (preferred)
• Alternative: Clarithromycin 500 mg BID + Ethambutol ± Rifabutin 300 mg/day
• Duration: ≥12 months + immune reconstitution (CD4 >100 cells/μL on ART for >6 months)
• ART initiation: Start within 2 weeks of MAC treatment initiation

• Indicated when CD4 <50 cells/μL
• Azithromycin 1200 mg once weekly (preferred) OR Clarithromycin 500 mg BID
• Can discontinue when CD4 ≥100 cells/μL sustained on ART for >3 months

Lymphadenitis

• Excision (complete excisional lymph node removal) is curative in most cases
• Antibiotics added for extensive/recurrent disease

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7. Drug Susceptibility Testing (DST)

• Macrolide susceptibility testing (clarithromycin MIC) is mandatory before and during treatment
• Macrolide resistance (clarithromycin MIC >32 μg/mL) = poor prognosis, requires alternative regimens
• Acquired resistance occurs via 23S rRNA mutations from macrolide monotherapy (never use as monotherapy)
• Routine susceptibility testing for rifamycins and ethambutol has limited clinical correlation, except for macrolides and amikacin

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8. Immune Reconstitution Inflammatory Syndrome (IRIS)

• In HIV patients starting ART while on MAC treatment
• Paradoxical worsening: fever, lymphadenopathy, new lesions
• Unmasking IRIS: MAC diagnosed after ART initiation reveals previously subclinical infection
• Management: Continue both ART and MAC treatment; NSAIDs; steroids for severe IRIS

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9. Complications

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10. Prognosis

• Immunocompetent pulmonary MAC: Variable; some patients with nodular-bronchiectatic disease have stable or slowly progressive course; fibrocavitary form is more aggressive with ~50% treatment success rates
• Disseminated MAC in HIV (pre-ART era): Median survival ~4–5 months; with ART + treatment, dramatically improved
• Post-ART era: Disseminated MAC is far less common; mortality related primarily to HIV disease control
• Macrolide-resistant MAC: Cure rates <30%
• Children with lymphadenitis: Excellent prognosis with surgical excision

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11. Prevention

• HIV patients: Primary MAC prophylaxis (azithromycin weekly) when CD4 <50 cells/μL
• ART: Most effective prevention strategy — immune reconstitution prevents disseminated MAC
• Environmental: No specific recommendations; avoid aerosolized water sources (hot tubs) in severely immunocompromised patients
• Surveillance and guideline updates via USPHS/IDSA and ATS/IDSA Joint Committees

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• Harrison's Principles of Internal Medicine, 21st Ed., p. 5254
• Prevention and Treatment of Opportunistic Infections in Adults/Adolescents with HIV (USPHS/IDSA), p. 460
• Prevention and Treatment of Opportunistic Infections in Children with and Exposed to HIV, p. 326
• ATS/IDSA NTM Guidelines (2007, updated 2020)